He Minghui, Cortizas Elena M, Verdun Ramiro E, Severinson Eva
Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden;
Division of Gerontology and Geriatric Medicine, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136;
J Immunol. 2015 May 1;194(9):4231-9. doi: 10.4049/jimmunol.1402146. Epub 2015 Mar 20.
Ig class switching requires cell proliferation and is division linked, but the detailed mechanism is unknown. By analyzing the first switching cells early in the kinetics, our analysis suggested that proliferating B cells had a very short G1 phase (<3.5 h), a total cell cycle time of ∼ 11 h, and that Ig class switching preferentially occurred in the late G1 or early S phase. Inhibition of cyclin-dependent kinases (CDKs) caused dramatic reduction of switching rate within 6 h. This was associated with less targeting of activation-induced cytidine deaminase (AID) to the Igh locus. Interestingly, ectopically expressed nuclear AID in HeLa cells was preferentially found in the early S phase. Furthermore, in CDK2 hypomorphic cells there was reduced nuclear AID accumulation. Thus, our data are compatible with the idea that division-linked Ig class switching is in part due to CDK2-regulated AID nuclear access at the G1/S border.
免疫球蛋白类别转换需要细胞增殖且与分裂相关，但具体机制尚不清楚。通过在动力学早期分析首批发生转换的细胞，我们的分析表明，增殖的B细胞G1期非常短（<3.5小时），总细胞周期时间约为11小时，并且免疫球蛋白类别转换优先发生在G1晚期或S早期。抑制细胞周期蛋白依赖性激酶（CDK）会在6小时内导致转换率显著降低。这与激活诱导的胞嘧啶脱氨酶（AID）对Igh基因座的靶向减少有关。有趣的是，在HeLa细胞中异位表达的核AID优先出现在S早期。此外，在CDK2低表达细胞中，核AID积累减少。因此，我们的数据与以下观点相符，即与分裂相关的免疫球蛋白类别转换部分归因于CDK2在G1/S边界调节AID进入细胞核。
